Objectives

1. Recognize the various pulmonary complications of radiation therapy.
2. Understand the diagnosis and treatment of radiation pneumonitis.
3. Learn about the spectrum of lung injury associated with different chemotherapy agents.
4. Review the mechanisms of injury (when known) in chemotherapy-induced lung disease.
5. Become familiar with the risk factors and the clinicopathologic, physiologic, and radiographic manifestations and treatment of lung injury associated with the different chemotherapeutic drugs.

Key words

chemotherapy lung toxicity; pulmonary toxicity from cancer drugs; radiation lung toxicity; toxic lung injury

Abbreviations

BOOP = bronchiolitis obliterans organizing pneumonia; HP = hypersensitivity pneumonitis; IL = interleukin; IP/F = interstitial pneumonitis/fibrosis; NCPE = noncardiogenic pulmonary edema; TGF-b = transforming growth factor-b; TNF = tumor necrosis factor

*Dr. Tietjen wrote the section on radiation-induced lung injury, and Dr. Stover prepared the section on chemotherapy-induced lung injury.

Advances in the treatment of cancer are made on a daily basis, with subsequent improvement in survival rates. However, new chemotherapeutic agents and improved radiation techniques are not without associated complications. The lung is particularly susceptible to the damaging effects of ionizing radiation, and the use of certain chemotherapeutic agents may potentiate this vulnerability. The adverse effects of radiation on the lung were first recognized in the late 19th century, and the clinical syndromes of radiation pneumonitis and radiation fibrosis were described in 1925.¹ Since these early observations, much has been learned about the mechanisms of action and injury of radiation therapy. Damage to healthy lung tissue remains the rate-limiting step in the delivery of radiation to the chest. The first part of this lesson will focus on risk factors, clinicopathologic features, physiologic/radiographic findings, and the treatment of radiation-induced lung injury. The second part will address chemotherapy-induced lung injury.

Radiation-Induced Lung Injury

Factors Affecting the Development of Radiation-Induced Lung Disease

Clinically evident radiation-induced lung injury occurs in 5 to 15% of patients receiving some form of radiotherapy to the chest.² Lung injury increases with the volume of lung tissue being irradiated. At least 10% of the lung needs to be irradiated to produce clinically significant pulmonary disease.³

The total dose of radiation delivered and the fractions at which it is delivered also influence the development of pneumonitis. A total radiation dose of < 20 Gy rarely results in clinically significant pulmonary toxicity, whereas doses > 60 Gy often do. Fractional doses given at different sessions during a day are safer than an equivalent dose given in a single session. Dose rate is also important, insofar as slower delivery rates are associated with a lower risk of developing pneumonitis.

Three-dimensional radiation therapy and the use of a total lung dose-volume histogram have been helpful in sparing irradiation to normal lung parenchyma and decreasing the incidence of radiation pneumonitis. In one study looking at the use of these parameters in the treatment of non-small cell lung cancer, the percentage of lung volume receiving radiation > 20 Gy, the total lung volume mean dose, and the location of the primary tumor (upper vs lower lobes) were significant factors in the development of radiation pneumonitis. The percentage of lung volume receiving radiation > 20 Gy also proved to be the single most significant predictor of pneumonitis.⁴

Patients receiving radiosensitizing chemotherapeutic agents such as bleomycin, cyclophosphamide, dactinomycin, vincristine, and recombinant interferon alpha are at increased risk of developing radiation pneumonitis. Concurrent administration of these agents while receiving radiation therapy is more harmful than their sequential usage.⁵

Host factors also play a role in the development of radiation-induced lung injury. In animal studies, there seem to be genetic differences in susceptibility to the effects of radiation,⁶ although no genetic marker has yet been identified in humans. Other factors that portend a poorer prognosis include younger age, female sex, prior chest wall irradiation, poor pretreatment performance status, and corticosteroid withdrawal. Patients with COPD seem to do more poorly when they develop radiation pneumonitis, but COPD has not been proven to be a risk factor for the development of radiation pneumonitis. The role of smoking in the development of radiation pneumonitis is not clear. Although many studies have reported smoking as a risk factor, one study suggested that smoking might actually be protective against the development of pneumonitis.⁷

Pathology

The pathologic changes in the lung after radiation treatment can be divided into various stages. The initial exposure to radiation results in vascular congestion of the small vessels with a resultant capillary leak syndrome. An exudative alveolitis occurs, and subsequently hyaline membranes develop. At the end of the first phase, approximately 1 to 2 months following the completion of radiation therapy, inflammatory infiltrates develop, again causing an increase in capillary permeability. During the second phase, 2 to 9 months after radiation therapy, the clinical syndrome recognized as radiation pneumonitis occurs. During this phase, there is accumulation of platelets, fibrin, and collagen in the pulmonary capillaries. Type II pneumocytes become hyperplastic and fibroblasts proliferate within the alveolar walls and spaces.⁸ These findings may resolve but if the damage is very severe, pulmonary fibrosis occurs. This final phase may become evident as early as 6 months following radiation, and it can progress for months to years. This late stage is characterized by fibrosis with increased numbers of myofibrils in the alveolar walls and spaces, subintimal vascular thickening, and luminal narrowing of capillaries.

A less commonly reported pattern of radiation-induced lung injury that resembles a hypersensitivity pneumonitis has been reported. This occurs after unilateral lung irradiation and is characterized by bilateral infiltrates, including areas outside of the field of radiation. It is an early complication of radiation therapy, and BAL fluid analysis has revealed a CD4+ lymphocytic alveolitis.⁹ Occurrence of radiation-induced hypersensitivity pneumonitis does not predict the occurrence of classic radiation pneumonitis.

Role of Cytokines

The pathologic changes described in classic radiation pneumonitis are mediated by a variety of cytokines. Immediately following radiation, tumor necrosis factor a (TNF-a) and interleukin-1a (IL-1a) levels are elevated. Shortly thereafter, the IL-6 level becomes elevated. One study found that elevated IL-6 prior to irradiation was a predictor of the development of radiation-induced lung injury. Transforming growth factor-b (TGF-b) is the main cytokine causing fibroblast collagen deposition. TGF-b is elevated prior to the development of clinically significant lung injury. Other cytokines that are upregulated at the same time include basic fibroblast growth factor and platelet derived growth factor.¹

Clinical Findings

Generally, the signs and symptoms of radiation pneumonitis develop insidiously but are usually evident by 6 to 12 weeks after the completion of radiation therapy (see Table 1). Earlier onset of symptoms is a poor prognostic indicator. Dyspnea on exertion or, in severe cases, at rest is the cardinal symptom. Other symptoms include cough, either nonproductive or minimally productive, chest pain, and fever. Hemoptysis is rare and usually a late finding. Symptoms of airway obstruction are usually not related to the radiation but to swelling of endobronchial tumors at the commencement of radiation. This may be treated with prophylactic corticosteroid therapy starting on the day prior to the initiation of radiation and continuing for the first few days of therapy.

Findings on auscultation of the lungs of patients who have undergone radiation therapy may be normal, but occasionally there may be rales or a pleural friction rub. Skin erythema corresponding to the area of irradiation is usually present but is not predictive of the development of radiation pneumonitis. In the most severe cases, tachypnea, cyanosis, and signs of cor pulmonale may be present.

Changes consistent with radiation fibrosis may occur over a 2-year period but usually remain stable after that. The late findings are related to the degree of fibrosis present and vary from asymptomatic to severe dyspnea with right-sided heart failure.

Diagnosis

The diagnosis of radiation pneumonitis may be made based on clinical findings occurring in the correct time frame, but recurrent malignancy and/or infection must be ruled out. Bronchoscopy with transbronchial biopsy may be helpful in ruling out alternative diagnoses, but the histologic findings of radiation pneumonitis are nonspecific and the amount of tissue obtained via transbronchial biopsy is usually too small to make a definitive diagnosis.

Pulmonary function testing, although not diagnostic, reveals some characteristic changes. Decreased lung compliance, reflected by a decrease in lung volumes (total lung capacity and FVC) and diffusing capacity, occurs approximately 2 months after radiation therapy and persists indefinitely. Gas exchange abnormalities including a decreased diffusing capacity and oxygen desaturation, especially upon exercise, may show some improvement over time.

There are no standardized laboratory tests available for diagnosing or predicting radiation pneumonitis. Sedimentation rate, lactate dehydrogenase level, and C-reactive protein level may all be elevated, but these findings are nonspecific. Several markers are presently under investigation. In one study, levels of TGF-b were elevated over baseline at the completion of therapy and were shown to be an independent risk factor for the development of radiation pneumonitis.¹⁰

Various radiographic modalities can be employed in the evaluation of the patient with radiation pneumonitis. Chest radiograph findings may initially be normal and then progress to diffuse haziness (Fig 1, top) or ground-glass opacities over the irradiated area. This may progress to alveolar infiltrates with or without air bronchograms (Fig 1, center), which are generally within the radiation portal. A straight-line effect (Fig 1, center) delineating the ports of radiation is virtually diagnostic of radiation-induced lung injury. In patients with fibrosis, there are linear streaks radiating from the areas of pneumonitis, causing contraction of the lung and volume loss (Fig 1, bottom).

CT scanning is usually not necessary unless other diagnoses, such as recurrent malignancy, are in question.^6,7 Ga citrate scanning is also a sensitive test for identifying active processes within the lung in the immunosuppressed host, but this test does not distinguish between radiation pneumonitis and other disorders such as infection or lymphangitic spread of cancer.

Figure 1. Top, increased interstitial markings in right hilar area 6 weeks after mediastinal radiation for non-Hodgkin’s lymphoma. Center, right hilar alveolar infiltrate with air bronchograms and straight-line sign that is not confined to anatomic boundaries. Bottom, pulmonary fibrosis 1 year after radiation treatment.

Treatment

There have been no prospective, controlled therapeutic trials for the treatment of radiation pneumonitis. Antibiotics, anticoagulants, and prophylactic corticosteroids have not been shown to improve outcome and therefore are not recommended. Several retrospective studies of corticosteroid treatment for symptomatic radiation pneumonitis seem to demonstrate a clinical benefit, although in other reports, severe pneumonitis was not improved with steroid therapy.¹¹ Most experts recommend treating symptomatic patients with prednisone at 1 mg/kg/d for several weeks followed by a slow steroid taper. A recent animal study showed a reduction in the incidence of radiation pneumonitis in animals treated with captopril.¹² A retrospective study in humans did not show the same benefit¹³; however, prospective studies using doses of the drug equivalent to those used in the animal studies have not been performed. There may be significant improvement in symptoms and lung function for 18 months to 2 years, but after this period, improvement is rare.

Radiation-Induced Bronchiolitis Obliterans Organizing Pneumonia

Bronchiolitis obliterans organizing pneumonia (BOOP) is a pattern of lung injury that can be idiopathic or related to various pulmonary insults, such as infection, drugs, collagen vascular diseases, and transplantation. There are also increasing reports of BOOP in patients with cancer.¹⁴ One group at risk is breast cancer patients receiving irradiation. Unlike patients with typical radiation pneumonitis, who present most commonly with dyspnea, patients with radiation-induced BOOP present with cough and fever. These findings generally occur within 12 months of completion of radiation therapy. Although the radiographic changes may begin on the irradiated side, they almost always progress out of the radiation portals, including the contralateral lung in 40% of patients.¹⁵ These patients generally respond well to corticosteroid therapy (prednisone at 1 mg/kg/d) but relapse rates can be as high as 67% when the steroids are tapered. The majority of cases of radiation-related BOOP have been reported in breast cancer patients, although there are also sporadic reports in patients with other malignancies. The reason for the preponderance in breast cancer patients is unclear. One group of investigators analyzed BAL fluid from a subset of breast cancer patients with BOOP and found the BAL fluid to be abnormal in all cases. Although this was a small study, 50% of patients had eosinophilia (> 5%), 80% had neutrophilia (> 5%), and 100% had lymphocytosis (> 20%). These patients initially respond well to corticosteroid therapy (prednisone at 1 mg/kg/d) but relapse rates are high, necessitating a very slow taper.¹⁶

Chemotherapy-Induced Lung Injury

When faced with the cancer patient who has new pulmonary signs, symptoms, or radiographic abnormalities, there is a broad spectrum of pathogens that must be considered. These include infectious agents, neoplastic disorders, and a wide variety of other injuries including pulmonary hemorrhage, cardiogenic and noncardiogenic pulmonary edema, graft-vs-host reactions, and radiation- and chemotherapy-induced lung injury (toxic lung injury). Perhaps the most challenging of these to diagnose is toxic lung injury because it can mimic both infectious and neoplastic lung disorders. Furthermore, if the toxicity goes unrecognized, continuing the offending agent may result in death. This section will review the mechanisms of lung injury (when known) and histopathologic findings associated with chemotherapeutic agents as well as the “risk factors,” clinical features, radiographic and physiologic findings, diagnosis, and treatment of the pulmonary abnormalities associated with these drugs. Although any drug has the potential to cause lung injury, the more common chemotherapeutic agents associated with pulmonary toxicity are listed in Table 2.

Clinicopathologic Syndromes

While much of the pathophysiology of toxic lung injury from specific agents is unknown, three common clinicopathologic syndromes have been associated with chemotherapyinduced lung injury: interstitial pneumonitis/fibrosis (IP/F), hypersensitivity pneumonitis (HP), and an acute pneumonitis with or without noncardiogenic pulmonary edema (NCPE). One could think of toxic lung injury as an imbalance that occurs in the lung among factors that keep it healthy.^2,17 For example, an upset in the balance between oxidants and antioxidants can result in damage. Certain cytotoxic drugs can trigger the formation of reactive oxygen metabolites such as superoxide anions, hydrogen peroxide, and hydroxyl radicals. These substances, in turn, can result in direct injury or they can initiate a metabolic cascade that produces immunoreactive substances, like prostaglandins and other cytokines, leading to inflammation and lung damage.

Cytotoxic drugs can also alter the balance between collagen formation and collagenolysis as well as the balance between effector and suppressor cells. The former may result in fibrosis through modulation of fibroblast proliferation and/or excessive collagen deposition, while the latter may result in a hypersensitivity reaction. NCPE is a lessrecognized toxic lung injury syndrome of anticancer therapy compared with IP/F or HP. Its pathophysiology remains unclear, but there are studies suggesting that both a direct cytotoxic insult to the lung epithelial cells and induction of a cytokine-triggered inflammatory response may be involved. Drug-induced interstitial pneumonitis can lead to permanent damage with fibrosis, whereas HP and NCPE are usually reversible. Commonly recognized clinicopathologic syndromes are discussed below and are all listed in Table 3 with their associated chemotherapeutic agents. Some drugs can cause more than one type of toxicity.

Interstitial pneumonitis/fibrosis

Bleomycin, the most well-recognized agent in this category, is an antitumor antibiotic used to treat a variety of neoplasms, including carcinoma of the head and neck, cervix, and esophagus, germ cell tumors, and Hodgkin’s and non- Hodgkin’s lymphoma.¹⁷ Its major limitation is its potential for causing life-threatening pneumonitis that can progress to fibrosis in up to 10% of patients receiving the drug.¹⁸ In one study of 180 patients treated for germ cell tumors between 1991 and 1995, the fatality rate from bleomycin-induced lung injury was 2.8%.¹⁹ Risk factors in this group of patients were age > 40 years and abnormal renal function.

The lack of an inactivating enzyme, bleomycin hydrolase, in the lung, may account for the specific lung toxicity of this agent. The central event in the development of bleomycininduced pneumonitis is endothelial damage with extravasation of fluid into the interstitial and alveolar spaces. There is destruction of type I pneumocytes along with proliferation of type II pneumocytes, which look bizarre and resemble hobnails. The latter finding is suggestive but not pathognomonic of chemotherapy-induced lung injury. The chronic fibrotic response to bleomycin is thought to be mediated by an immunologic mechanism in which tumor necrosis factor (TNF), derived from the alveolar macrophage, plays a key role.²⁰ Evidence supporting the role of TNF in the pathogenesis of bleomycin pneumonitis is the fact that animals whose TNF receptors have been deleted are protected from the development of injury and fibrosis. Other forms of lung injury, such as HP, pulmonary nodules, and BOOP, have been reported with bleomycin but less commonly.¹⁷

Factors associated with an increased risk of bleomycin interstitial pneumonitis include advanced age, higher doses, abnormal renal function, and concurrent or subsequent use of oxygen, radiation therapy, and other chemotherapeutic agents (see Table 4). Although administration of higher doses clearly increases the risk of lung toxicity, injury can occur at doses < 50 mg/m². Concentrations of inspired oxygen increase the risk of developing bleomycin toxicity. Whether there is a threshold fraction of inspired oxygen, duration of therapy, or interval following bleomycin treatment after which higher oxygen concentrations will not increase the risk of lung injury is unknown. Previous or simultaneous thoracic irradiation increases the risk of toxicity; however, as is the case with oxygen therapy, it is not known whether a long interval between irradiation and administration of bleomycin eliminates the risk. Although earlier reports identified concomitant treatments with granulocyte colony-stimulating factor as a possible risk factor, recent studies have shown no increase in pulmonary toxicity when granulocyte colony-stimulating factor is co-administered.²¹

The clinical presentation of bleomycin toxicity usually begins between 1 and 6 months after bleomycin treatment. Symptoms, physical signs, and pulmonary function abnormalities are nonspecific and include the following: insidious onset of dyspnea, dry cough, fever, tachypnea, “Velcro” rales, a decrease in diffusing capacity out of proportion to the lung volumes (which may be normal or restricted), and hypoxemia, particularly with exercise. An acute chest pain syndrome affecting approximately 1% of patients during the infusion of bleomycin has been described but does not predict the development of pulmonary fibrosis. The classic chest radiograph shows reticular densities at the bases and peripherally; these findings can progress to consolidation with honeycombing. The major advantage of chest CT is that it better defines the subpleural location of the infiltrates. Rounded masses on chest radiograph or CT scan may mimic metastatic disease and often present a diagnostic dilemma.¹⁷

Most important in the treatment of bleomycin toxicity is recognition of the syndrome and discontinuation of the drug. Avoidance of oxygen and/or subsequent thoracic irradiation is important in the treatment. Although there are no specific studies addressing the efficacy, effective dose, or optimal duration of corticosteroid therapy, short-term improvement occurs in 50 to 70% of treated patients.²² It is our practice to initiate treatment with 1 mg/kg of prednisone and taper the dose over a period of at least 3 to 6 months. In most cases, Pneumocystis carinii prophylaxis should be given because of the prolonged period of steroid use. Because symptoms may relapse when therapy is tapered and then become more difficult to control, the patient should be closely monitored during prednisone tapering. It is unclear whether screening pulmonary function tests are useful in the assessment of patients during bleomycin therapy because both false-positive and false-negative results have been reported. However, during the tapering of prednisone, it is our practice to follow both the diffusing capacity and the rest and exercise oximetry. If either deteriorates during the taper, prednisone is increased, usually to the previous dose, and continued until stabilization occurs.

Other drugs known to cause IP/F lung injury are listed in Table 3. Although mitomycin C can cause a histopathologic picture similar to that caused by bleomycin, it has been associated with several other pulmonary disorders that will be discussed later. The mechanism of injury from these drugs is unknown, but in most cases it is thought to occur from direct injury to the epithelial lining cells through production of toxic oxygen species. The interval between initiation of therapy and onset of pulmonary symptoms with busulfan, cyclophosphamide, chlorambucil, and the nitrosoureas can be very long, sometimes > 10 years after exposure to the drug. Symptomatic pulmonary injury is estimated to occur in < 5% of patients receiving these drugs with the exception of carmustine (BCNU). One study of 94 Hodgkin’s lymphoma patients receiving carmustine reported early-onset interstitial pneumonitis in up to 47% of the patients whose doses were > 535 mg/m2 and 26% of these patients died, whereas 15% developed toxicity at doses < 475 mg/m2. Statistical analysis revealed that the only independent variables associated with lung disease were total dose of carmustine and female sex.²³ Late-onset carmustine lung fibrosis has been reported in survivors of childhood brain tumors; after 16 to 20 years of follow-up, 8 of 17 patients died of pulmonary fibrosis.²⁴ As with idiopathic fibrosis, no treatment is effective for late-onset carmustine lung injury. Lung transplant offers the best hope of long-term survival.

Factors associated with an increased risk of toxicity from these drugs are listed in Table 4. Because cytologic and pathologic findings associated with these chemotherapeutic agents are nonspecific, as with bleomycin, the diagnosis of toxicity is usually established clinically and is one of exclusion. As with all drug-induced pulmonary toxicity, withdrawal of the drug is the mainstay of treatment. Although there are no controlled studies evaluating the usefulness of corticosteroids, patients are usually given prednisone at a dose of 1 mg/kg of body weight. If there is a response, the corticosteroids are tapered slowly over a 3- to 6-month period.

Hypersensitivity pneumonitis

Although a number of chemotherapeutic agents have been associated with HP, methotrexate is the most common drug associated with this pattern. Methotrexate has anti-inflammatory and immunomodulating properties in addition to its antiproliferative effects, and it is used in the treatment of many solid and hematologic malignancies. A number of adverse effects may result from the use of methotrexate, including serious toxicity to the liver, bone marrow, and lungs. The precise frequency with which methotrexate pulmonary injury occurs is difficult to ascertain because many reports have included patients who are receiving other cytotoxic agents. It is estimated that pulmonary toxicity develops in 2 to 8% of patients receiving methotrexate, but some reports suggest an incidence as high as 33%.¹⁷

The precise mechanism of methotrexate pulmonary injury is unknown. Studies suggest that it is a form of HP because of the increased number of lymphocytes and sometimes eosinophils seen in BAL fluid and a mononuclear cell infiltration of the lung with poorly formed noncaseating granuloma.^25,26 Other studies suggest that the injury may be from a direct toxic effect on lung tissue with diffuse alveolar damage and perivascular inflammation.²⁶ Methotrexate pulmonary toxicity usually occurs in close proximity to receiving the drug, but cases have been reported as late as 18 years after discontinuing it.

The clinical presentation can be acute with fever, chills, malaise, headache, cough, and dyspnea.²⁷ Interestingly, while methotrexate has been used to treat the inflammatory component of asthma, there are reports that it can induce bronchitis and bronchial hyperreactivity. Radiographically, the earliest findings are interstitial opacities, which may progress to alveolar infiltrates with patchy consolidation. Nodular opacities or illdefined acinar shadows may be diffusely scattered throughout the lungs.²⁸

Other drugs that have been associated with HP include azathioprine, procarbazine, bleomycin, and possibly paclitaxel, which will be discussed later.

Noncardiogenic pulmonary edema

Drug-induced NCPE produces endothelial inflammation and capillary leak. It is usually associated with an acute pneumonitis syndrome and pathologic examination reveals diffuse alveolar damage. Drugs associated with NCPE include mitomycin C in association with a vinca alkaloid, cytosine arabinoside, all-transretinoic acid, IL-2, and gemcitabine. The drug most commonly associated with this type of lung injury has been mitomycin C when it is temporally related to the administration of a vinca alkaloid. One study of 387 patients found a 6% incidence of toxic lung injury following combination chemotherapy using mitomycin C and vinblastine in patients with advanced non-small cell lung cancer.²⁹ The syndrome was characterized by sudden onset of dyspnea, new focal or diffuse interstitial infiltrates on chest radiograph, severe hypoxemia, and, when available, pulmonary function tests showing severely impaired diffusing capacity. There was a partial response to corticosteroid therapy, but 60% of patients experienced chronic respiratory impairment despite initial improvement. Other studies have reported dramatic improvement after the administration of corticosteroids in mitomycin C-associated acute interstitial pneumonitis. Response to therapy probably depends on the presence and degree of diffuse alveolar damage and subsequent development of interstitial pulmonary fibrosis.

Thrombotic microangiopathy and ARDS have been associated with mitomycin C in a small number of cases. Its occurrence is directly related to the total dose of mitomycin C administered. Patients receiving 5-fluorouracil or blood transfusions before starting mitomycin C appear to have an increase in the risk of this syndrome. It occurs during or shortly after completion of chemotherapy and is characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal insufficiency, and acute lung injury with respiratory failure in approximately 50% of cases. Patients who develop ARDS have a higher mortality rate than similar patients who do not have ARDS (95 vs 50%). The pathogenesis of this syndrome is not known, but it is thought to result from the release of toxic cell products resulting in endothelial damage in response to mitomycin C. The response to treatment with corticosteroids, dialysis, and/or plasmapheresis is poor, with a mortality rate of 70% in one series.³⁰

There have been rare reports of gemcitabine causing a capillary leak syndrome that is not dose dependent.³¹ Dyspnea may be subtle or acute in onset. Chest radiograph findings can vary from ground-glass infiltrates to fulminant pulmonary edema. Clinical suspicion with exclusion of other causes of lung injury should suggest the diagnosis. Early recognition, drug withdrawal, and corticosteroids are the main therapeutic measures.

Other clinicopathologic syndromes

BOOP, intra-alveolar pulmonary hemorrhage, and airways disease with bronchospasm are less common modalities of lung injury induced by chemotherapeutic agents. Although BOOP is uncommonly associated with chemotherapy injury, recently it has been reported in more than 40 cases of women receiving irradiation for breast cancer (see “Radiation-Induced Lung Injury”). Etoposide (VP-16) has been reported to cause intraparenchymal pulmonary hemorrhage after highdose chemotherapy with bone marrow or stem cell transplants for breast cancer.³² In combination with mitomycin C, vinca alkaloids can cause parenchymal lung disease, but alone, they have been reported to cause wheezing with normal chest radiographs.

Besides causing interstitial pneumonitis and HP, paclitaxel has been reported to cause an anaphylactoid reaction.^33-36 This type of hypersensitivity reaction is thought to be due to direct injury to basophils with histamine release resulting in bronchospasm, urticaria, and occasionally angioedema with hypotension. The suspension vehicle (Cremophor EL, in Taxol; Bristol-Myers Squibb Co; New York, NY) is thought to cause this syndrome rather than paclitaxel itself. Prophylaxis with corticosteroids, administration of H1 and H2 histamine blockers, and a slow infusion rate are effective in reducing the incidence and severity of this reaction.

All-trans-retinoic acid treatment of acute promyelocytic leukemia induces a distinct syndrome of respiratory distress. It is thought to be mediated by newly differentiated leukemia cells that are marginating into the pulmonary circulation, causing an increase in capillary permeability and a release of cytokines that induce neutrophil migration into the interstitium. The syndrome is characterized by significant weight gain, pericardial and pleural effusions, pulmonary edema, and ascites. High doses of corticosteroids are the most effective treatment; steroid prophylaxis has significantly decreased this syndrome’s high mortality rate.³⁷

Recently, four patients developed interstitial pneumonitis that could be explained only by toxicity to docetaxel.³⁸ Two patients died despite broad-spectrum antibiotics and corticosteroids, and the two survivors required long-term ventilatory support. Pulmonary veno-occlusive disease rarely has been associated with some chemotherapeutic agents, most recently with gemcitabine³⁹ (see Table 3).

Conclusion

It should be remembered that any drug has the potential to cause lung injury. When dealing with cancer patients and others receiving chemotherapy, a high index of clinical suspicion should be maintained for chemotherapy-induced lung toxicity when pulmonary signs and symptoms occur. Familiarity with the different clinicopathologic syndromes is essential for early recognition and proper management of these patients.

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